The present invention relates to the use of 2-substituted adenosine carboxamide derivatives in the diagnosis of myocardial dysfunction by electrophysiologic analysis or by imaging the vasculature of the heart, especially under conditions that simulate stress.
Adenosine has been known since the early 1920""s to have potent vasodilator activity. It is a local hormone released from most tissues in the body during stress, especially hypoxic and ischemic stress (see Olsson et al., Physiological Reviews, 70(3), 761-845, 1990). As such, adenosine and adenosine-releasing agents are now commonly used to simulate the stress condition for diagnostic purposes (see The Medical Letter, 33(853), 1991).
Thallium-201 myocardial perfusion imaging is currently the most common approach in the use of stress-simulating agents as a means of imaging the coronary vessels to obtain a diagnosis of coronary artery disease. This is effected by injection of the stress agent such as adenesine at a dose of about 1 mg/kg body weight, followed by injection of the radionuclide, thallium-201, and scanning with a rotating gamma counter to image the heart and generate a scintigraph (see McNulty, Cardiovascular Nursing, 28(4), 24-29, 1992).
The mechanism underlying thallium-201 myocardial perfusion imaging is as follows: adenosine acting on coronary adenosine receptors causes relaxation of the coronary arterioles, thereby increasing blood flow throughout the heart. This effect is short-lasting and at a dose of 1 mg/kg, adenosine does not dilate other peripheral blood vessels to produce substantial systemic hypotension. Diseased or otherwise blocked coronary vessels will not further dilate in response to adenosine and the subsequent flow of thallium-201 through the heart will be less in these regions of hypoperfusion relative to other more normal areas of the heart. The resulting image allows the diagnostitian to quantitate the amount and severity of the coronary perfusion defect. This analysis is of paramount importance in selecting any further course of therapy and intervention by the physician [See U.S. Pat. No. 5,070,877 (Mohiuddin et al.) and U.S. Pat. No. 4,824,660 (Angello et al.)].
The use of adenosine and like-acting analogs is associated with certain side-effects. Adenosine acts on at least two subclasses of adenosine receptors, A1 or A2, both of which are found in the heart. The A1 receptor subtype, when activated by adenosine, among other actions, slows the frequency and conduction velocity of the electrical activity that initiates the heart beat. Sometimes adenosine, particularly at doses near 1 mg/kg, even blocks (stops) the heart beat during this diagnostic procedurexe2x80x94a highly undesirable action. The A2 receptor subtype is found in blood vessels and is further divided into A2a and A2b receptor subtypes (see Martin et al., Journal of Pharmacology and Experimental Therapeutics, 265(1), 248-253, 1993). It is the A2a receptor that is specifically responsible for mediating coronary vasodilationxe2x80x94the desired action of adenosine in the diagnostic procedure. Thus, the side-effects of adenosine and adenosine releasing agents result substantially from non-selective stimulation of the various adenosine receptor subtypes. Clearly, a better procedure would be to use a substance as a stress agent that selectively activates only the A2a receptor, is short acting and works at doses substantially below 1 mg/kg body weight.
U.S. Pat. No. 5,477,857 to McAfee et al. discloses various diagnostic uses of hydrazinoadenosines. The compounds described in the McAfee patent are extremely effective for perfusion imaging, but suffer from a few limitations. Several of the compounds McAfee discloses as being useful are extremely labile, and prone to hydrolysis in vivo. For this reason, they have extremely short half-lives in vivo, and also must be stored in lyophilized form. Further, it is believed that one of the degradation processes for adenosine derivatives involves de-ribosylation of the derivative to form an adenine derivative, which can potentially be incorporated into genetic material of patients to whom they are administered. When using adenosine derivatives instead of adenosine, it would be advantageous to use compounds which are relatively more hydrophobic, and therefore, less likely to be absorbed by the cells, than adenosine derivatives which are commonly used.
It would be advantageous to provide perfusion imaging methods which overcome these limitations. The present invention provides such methods.
This invention is directed to the administration of 2-substituted adenosine carboxamide derivatives as a pharmacological stressor in conjunction with any one of several noninvasive diagnostic procedures available. For example, intravenous administration may be used in conjunction with thallium-201 myocardial perfusion imaging to assess the severity of myocardial ischemia.
Any one of several different radiopharmaceuticals may be substituted for thallium-201 (e.g., rubidium-82, technetium 99 m, derivatives of technetium 99 m, nitrogen-13, iodine 123, etc.). Similarly, the 2-substituted adenosine carboxamide derivatives may be administered as a pharmacological stressor in conjunction with radionuclide angiography to assess the severity of myocardial dysfunction. In this case, radionuclide angiographic studies may be first pass or gated equilibrium studies of the right and/or left ventricle. Similarly, the compounds may be administered as a pharmacological stressor in conjunction with echocardiography to assess the presence of regional wall motion abnormalities. Similarly, the 2-substituted adenosine carboxamide derivatives may be administered as a pharmacological stressor in conjunction with invasive measurements of coronary blood flow such as by intracardiac catheter to assess the functional significance of stenotic coronary vessels.
The methods described herein use specific compounds having activity as A2 adenosine receptor agonists, namely 2-substituted adenosine carboxamide derivatives. The method involves using one or more of the compounds described herein as a substitute for exercise in conjunction with imaging to detect the presence and/or assess the severity of ischemic ventricular dysfunction in humans wherein ischemic ventricular dysfunction is measured by any one of several imaging techniques including echocardiography, contrast ventriculography, or radionuclide angiography.
It is essential that the compounds herein be capable of binding selectively to A2 adenosine receptors, e.g., in a human. Methods for determining whether compounds bind selectively to A2 adenosine receptors, e.g., in a human, are well known to those of skill in the art, and include, for example, competitive binding studies. Suitable competitive binding studies are disclosed in the Examples section.
The following definitions will be useful in understanding the compounds and methods described herein.
As used herein, a compound is selective for the A2 receptors if the ratio of A2/A1 and A2/A3 activity is greater than about 20, preferably between 50 and 100, and more preferably, greater than about 100.
As used herein, the term xe2x80x9clowerxe2x80x9d referred to above and hereinafter in connection with organic radicals or compounds respectively defines such with up to and including 7, preferably up to and including 4 and advantageously one or two carbon atoms.
As used herein, the term xe2x80x9calkylxe2x80x9d refers to monovalent straight, branched or cyclic alkyl groups preferably having from 1 to 20 carbon atoms (xe2x80x9calkylxe2x80x9d). A lower alkyl group is straight chain or branched and preferably contains 1 to 4 carbon atoms, and represents for example ethyl, propyl, butyl, and advantageously methyl.
This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, -butyl, iso-butyl, n-hexyl, and the like. The terms xe2x80x9calkylenexe2x80x9d and xe2x80x9clower alkylenexe2x80x9d refer to divalent radicals of the corresponding alkane. Further, as used herein, other moieties having names derived from alkanes, such as alkoxyl, alkanoyl, alkenyl, cycloalkenyl, etc. when modified by xe2x80x9clower,xe2x80x9d have carbon chains of ten or less carbon atoms. In those cases where the minimum number of carbons are greater than one, e.g., alkenyl (minimum of two carbons) and cycloalkyl, (minimum of three carbons), it is to be understood that xe2x80x9clowerxe2x80x9d means at least the minimum number of carbons.
As used herein, xe2x80x9calkarylxe2x80x9d refers to an alkyl group with an aryl substituent. Binding is through the aryl group. xe2x80x9cAralkylxe2x80x9d refers to an aryl group with an alkyl substituent, where binding is through the alkyl group. These terms are analogously described with respect to aralkoxy and alkaryloxy, and other terms with similar description of linkages between aryl and alkyl groups.
As used herein, the term xe2x80x9calkoxyxe2x80x9d refers to the group xe2x80x9calkyl-O-xe2x80x9d, where alkyl is as defined above. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. A lower alkoxy group is straight chain or branched and preferably contains 1 to 4 carbon atoms, and represents for example methoxy, ethoxy, propoxy.
Lower alkylene is straight chain or branched alkylene and preferably contains 1 to 4 carbon atoms, and represents for example methylene, ethylene.
Lower alkenylene is straight chain or branched alkenylene; preferably contains 2 to 4 carbon atoms and represents for example ethenylene, 1- or 2-propenylene.
Aryl is an optionally substituted carbocyclic or heterocyclic aromatic radical, a carbocyclic aromatic radical being preferably phenyl or 1- or 2-naphthyl each optionally substituted by one to three of lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl, or by a substituent xe2x80x94Wxe2x80x94Z in which W represents a direct bond, lower alkylene, thio-lower alkylene or oxy-lower alkylene and Z represents cyano, carboxy or carboxy derivatized in the form of a pharmaceutically acceptable ester or amide; and a heterocyclic aromatic radical being preferably pyridyl or thienyl. Advantageously aryl represents phenyl or phenyl substituted as described above.
Examples of aryl groups include unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can further optionally be substituted with from 1 to 5 substituents and preferably 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, -SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-heteroaryl, trihalomethyl. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
Aryl-lower alkyl represents preferably aryl-C1-C4-alkyl in which aryl represents a carbocyclic or heterocyclic aromatic radical as defined above, e.g. benzyl or 1- or 2-phenyl-(ethyl, propyl or butyl), each unsubstituted or substituted on phenyl ring as defined under aryl above; or 2-, 3- or 4-pyridylmethyl or 2-(2-, 3- or 4-pyridyl)-(ethyl, propyl or butyl); or 1- or 2-naphthylmethyl or 2-(1- or 2-naphthyl)-(ethyl, propyl or butyl).
Aryl-hydroxy-lower alkyl represents preferably aryl-hydroxy-C1-C4-alkyl in which aryl preferably represents a carbocyclic aromatic radical as defined above, e.g. 2-phenyl-2-hydroxy-(ethyl, propyl or butyl).
Diaryl-lower alkyl represents preferably diphenyl-C1-C4-alkyl, e.g. omega-diphenyl- (methyl, ethyl or propyl).
As used herein, the term xe2x80x9ccycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 12 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantyl, and the like. Cycloalkyl preferably represents 3 to 6 ring membered cycloalkyl, i.e. C3-C6-cycloalkyl. C3-C6-cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.
Cycloalkyl-lower alkyl represents preferably (cyclopentyl or cyclohexyl)-C1-C4-alkyl, advantageously 1- or 2-(cyclopentyl or cyclohexyl)-ethyl, propyl or butyl.
Bicycloalkyl represents preferably bicycloheptyl or bicycloheptyl substituted by lower alkyl, particularly unsubstituted or lower alkyl substituted bicyclo[2,2,1]-heptyl, such as bornyl, neobornyl, isobornyl, norbornyl, e.g. 2-norbornyl. The term bornyl is synonymous with bornanyl.
Cycloalkenyl-lower alkyl represents preferably 1-cyclohexenyl-lower alkyl.
As used herein, the term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic carbocyclic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring).
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with from 1 to 5 substituents and preferably 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-heteroaryl, and trihalomethyl. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 15 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen within the ring.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy, trihalomethyl, and the like. Such heterocyclic groups can have a single ring or multiple condensed rings.
As to any of the above groups that contain 1 or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
The term xe2x80x9cprotecting groupxe2x80x9d or xe2x80x9cblocking groupxe2x80x9d refers to any group which when bound to one or more hydroxyl, amino or carboxyl groups of the compounds (including intermediates thereof such as the aminolactams, aminolactones, etc.) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, amino or carboxyl group. Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), and the like which can be removed by conventional conditions compatible with the nature of the product.
As used herein, the term xe2x80x9chalogenxe2x80x9d refers to bromide, chloride, fluoride and iodide radicals.
Halogen is preferably chloro, but may also be fluoro, bromo or iodo.
Tetrahydropyranyl represents preferably 4-tetrahydropyranyl.
Tetrahydrothiopyranyl represents preferably 4-tetrahydrothiopyranyl.
Bicycloalkenyl represents preferably bicycloheptenyl or bicycloheptenyl substituted by lower alkyl, particularly unsubstituted or lower alkyl-substituted bicyclo[2.2.1]heptenyl, such as 5-norbornen-2-yl, or unsubstituted or lower alkyl-substituted bicyclo[3.1.1]heptenyl, such as 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl.
Adamantyl represents preferably 1-adamantyl.
Hydroxy-lower alkyl represents preferably 2-, 3- or 4-hydroxy-C2-C4-alkyl, advantageously hydroxyethyl.
Pyridyl represents 2-, 3- or 4-pyridyl, advantageously 2- or 3-pyridyl.
Thienyl represents 2- or 3-thienyl.
Aryl-cycloalkyl represents preferably phenyl-C3-C6-cycloalkyl, for example 2-phenylcyclohexyl or 2-phenylcyclopropyl.
A bicyclic benzo-fused 5- or 6-membered saturated carbocyclic radical, as a substituent R1 depicted by formula B above in which A represents methylene, represents preferably 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl, each unsubstituted or substituted on benzo portion as indicated above for phenyl under aryl.
A bicyclic benzo-fused 5- or 6-membered saturated heterocyclic radical, as a substituent depicted by formula B above in which A represents oxy or thio, represents preferably 3,4-dihydro-2H-[1]-3-benzopyranyl or 3,4-dihydro-2H-[1]-3-benzothiopyranyl, each unsubstituted or substituted on the benzo portion as indicated above for phenyl under aryl.
A lower alkoxycarbonyl group preferably contains 1-4 carbon atoms in the alkoxy portion and represents for example: methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or advantageously ethoxycarbonyl.
Lower alkanoyl represents preferably straight chain or branched C1-C4-alkanoyl, e.g. acetyl, isobutyryl, pivaloyl.
Lower alkoxy-lower alkanoyl represents preferably lower alkoxy-C2-C4-alkanoyl, e.g. methoxyacetyl, 3-ethoxypropionyl.
Aroyl represents preferably benzoyl, benzoyl substituted by one to three of lower alkyl, lower alkoxy, halogen or trifluoromethyl; 2-, 3- or 4-pyridylcarbonyl; or 2- or 3-thienylcarbonyl.
Mono- and di-lower alkylcarbamoyl represents for example N-methyl-, N-ethyl-, N,N-dimethyl- and N,N-diethylcarbamoyl.
Carboxy esterified in the form of a pharmaceutically acceptable ester represents advantageously an ester that may be convertible by solvolysis or under physiological conditions to the free carboxylic acid, e.g. lower alkoxycarbonyl; (amino, mono- or di-lower alkylamino)substituted lower alkoxycarbonyl; carboxy substituted lower alkoxycarbonyl, e.g. alpha-carboxy-substituted lower alkoxycarbonyl; lower alkoxycarbonyl-substituted lower alkoxycarbonyl, e.g. alpha-lower alkoxycarbonyl-substituted lower alkoxycarbonyl; aryl-substituted lower alkoxycarbonyl, e.g. optionally substituted benzyloxy carbonyl or pyridylmethoxycarbonyl; (hydroxy, lower alkanoyloxy or lower alkoxy)-substituted lower alkoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl; (hydroxy, lower alkanoyloxy or lower alkoxy)-substituted lower alkoxymethoxycarbonyl; bicycloalkoxycarbonyl-substituted lower alkoxycarbonyl, e.g. bicyclo[2,2,1]-heptyloxycarbonyl-substituted lower alkoxycarbonyl, especially bicyclo [2,2,1]heptyloxycarbonyl-substituted methoxycarbonyl such as bornyloxycarbonylmethoxycarbonyl; 3-phthalidoxycarbonyl; (lower alkyl, lower alkoxy, halo)-substituted 3-phthalidoxycarbonyl; lower alkoxycarbonyloxy-lower alkoxycarbonyl, e.g. 1-(methoxy- or ethoxycarbonyloxy)-ethoxycarbonyl; aryloxycarbonyl, e.g. phenoxycarbonyl or phenoxycarbonyl advantageously substituted at the ortho position by carboxy or lower alkoxycarbonyl. Preferred are the lower alkyl esters, omega-(di-lower alkylamino)-alkyl esters, e.g. the di-(C1-C4-alkylamino)-ethyl esters, and pivaloyloxymethyl esters.
Carboxy derivatized in the form of a pharmaceutically acceptable amide represents preferably carbamoyl, mono-lower alkylcarbamoyl or di-lower alkylcarbamoyl.
Carboxy derivatized in form of a pharmaceutically acceptable amide further represents C1-C2O-alkylcarbamoyl, di-C1-C2O-alkyl-carbamoyl, aryl-lower alkylcarbamoyl, di-lower alkylamino-lower alkylcarbamoyl, (pyrrolidino, piperidino or morpholino)-lower alkylcarbamoyl, 2-oxopyrrolidino-lower alkylcarbamoyl, morpholinocarbonyl, piperidinocarbonyl unsubstituted or substituted with aryl-lower alkyl, aryl, or lower alkylcarbonyl, or piperazinocarbonyl substituted at the 4-position with aryl-lower alkyl, aryl or lower alkylcarbonyl. Aryl in the above represents preferably phenyl, phenyl substituted by lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl, or heteroaryl such as indolyl (advantageously 3-indolyl) or pyridyl.
The pharmaceutically acceptable ester derivatives in which one or more free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester are particularly prodrug esters that may be convertible by solvolysis under physiological conditions to the compounds of formula I having free hydroxy groups.
Preferred as said prodrug pharmaceutically acceptable esters are straight chain or branched lower alkanoic acid esters, e.g., the acetic, isobutyric, pivaloic acid esters; lower alkoxy-lower alkanoic acid esters, e.g., the methoxyacetic, 3-ethoxypropionic acid esters; arylcarboxylic acid esters, e.g., the benzoic, nicotinic acid esters; carbamic and mono or di-lower alkylcarbamic acid esters (carbamates), e.g. the mono- or di-ethylcarbamic or N-mono- or di-methylcarbamic acid esters. Most preferred are the lower alkanoic acid and lower alkoxyalkanoic acid esters.
Pharmaceutically acceptable salts are generally acid addition salts, which are preferably such of therapeutically acceptable inorganic or organic acids, such as strong mineral acids, for example hydrohalic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, gluconic, citric, maleic, fumaric, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic, cyclohexylsulfamic acid; or ascorbic acid. For compounds having a free carboxy group, pharmaceutically acceptable salts are also derived from bases, e.g. alkali metal salts, such as the sodium salt, or salts derived from pharmaceutically acceptable amines, such as tromethamine.
The following abbreviations are used herein: Abbreviations: [125I]AB-MECA, [125I]N6-(4-amino-3-iodobenzyl)adenosine-5xe2x80x2N-methyluronamide;(R)-PIA, (R)-N6-(phenylisopropyl)adenosine; DMSO, dimethysulfoxide; I-AB-MECA, N6-(4-amino-3-iodobenzyl)adenosine-5xe2x80x2-N-methyluronamide; IB-MECA, N6-(3-iodobenzyl)adenosine-5xe2x80x2-N-methyluronamide; Ki, equilibrium inhibition constant; NECA, 5xe2x80x2-N-ethylcarboxamido adenosine; THF, tetrahydrofuran; Tris, tris(hydroxymethyl)aminomethane.
The compounds have the following structural formula: Compounds of the formula I 
wherein R represents hydrogen or lower alkyl; R1 represents C3-C6-cycloalkyl optionally substituted by lower alkyl, C3-C6-cycloalkyl-lower alkyl optionally substituted by lower alkyl, bicycloalkyl, bicycloalkyl-lower alkyl, aryl, aryl-lower alkyl, aryl-C3-C6-cycloalkyl, 9-fluorenyl, diaryl-lower alkyl, 9-fluorenyl-lower alkyl, cycloalkenyl-lower alkyl, bicycloalkenyl-lower alkyl, tetrahydropyranyl-lower alkyl, tetrahydrothio-pyranyl-lower alkyl or adamantyl-lower alkyl: or R1 represents a bicyclic benzo-fused 5- or 6-membered saturated carbocyclic radical or a benzo-fused 5- or 6-membered saturated heterocyclic radical containing a heteroatom selected from oxygen and sulfur which is directly attached to the fused benzene ring, any said bicyclic radical being unsubstituted or substituted on the benzo portion by lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl, or by a substituent xe2x80x94Wxe2x80x94Z in which W represents a direct bond, lower alkylene, lower alkenylene, thio-lower alkylene or oxy-lower alkylene and Z represents cyano, carboxy or carboxy derivatized in the form of a pharmaceutically acceptable ester or amide, or R1 represents any said bicyclic radical substituted-lower alkyl; or R1 represents aryl-hydroxy lower alkyl; R2 represents hydrogen, lower alkyl or aryl-lower alkyl; R3 represents hydrogen or hydroxy; R4 represents hydrogen, lower alkyl, aryl-lower alkyl, C3-C6-cycloalkyl or hydroxy-lower alkyl; aryl represents an optionally substituted carbocyclic aromatic radical, being preferably 1- or 2-naphthyl, phenyl, or naphthyl or phenyl substituted by one to three of lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl, or naphthyl or phenyl substituted by a substituent xe2x80x94Wxe2x80x94Z in which W represents a direct bond, lower alkylene, lower alkenylene, thio-lower alkylene or oxy-lower alkylene and Z represents cyano, carboxy or carboxy derivatized in the form of a pharmaceutically acceptable ester or amide; or aryl represents a heterocyclic aromatic radical, being preferably pyridyl or thienyl, each optionally substituted as described above for phenyl; pharmaceutically acceptable ester derivatives thereof in which free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof.
Preferred are the compounds of formula I wherein R represents hydrogen or lower alkyl; R1 represents C3-C6-cycloalkyl-lower alkyl; or R1 represents aryl-lower alkyl wherein aryl represents pyridyl, thienyl, naphthyl, phenyl, phenyl substituted by one or two substituents selected from halogen, trifluoromethyl, lower alkoxy, hydroxy and lower alkyl, or phenyl substituted by a substituent xe2x80x94Wxe2x80x94Z in which W represents a direct bond, lower alkylene, lower alkenylene, thio-lower alkylene or oxy-lower alkylene, and Z represents cyano, carboxy, carboxy derivatized in the form of a pharmaceutically acceptable ester or carboxy derivatized in the form of a pharmaceutically acceptable amide; or R1 represents a substituent of the formula B 
in which A represents methylene, oxy or thio, n represents zero or one, p represents zero, one or two, and Ra represents hydrogen, lower alkyl, lower alkoxy, halogen or xe2x80x94Wxe2x80x94Z as defined above; R2 represents hydrogen or lower alkyl; R3 represents hydrogen or hydroxy; R4 represents hydrogen, lower alkyl, C3-C6-cycloalkyl, hydroxy-lower alkyl, or aryl-lower alkyl in which aryl represents pyridyl, thienyl or phenyl; pharmaceutically acceptable ester derivatives thereof in which one or more free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof.
Preferred are the compounds of formula (Ia) 
wherein Rxe2x80x2 represents hydrogen or lower alkyl; R1xe2x80x2 represents C3-C6-cycloalkyl-lower alkyl; or R1xe2x80x2 represents aryl-lower alkyl in which aryl represents thienyl, pyridyl, phenyl or phenyl monosubstituted by halogen, trifluoromethyl, lower alkoxy, hydroxy, lower alkyl, or by a substituent xe2x80x94Wxe2x80x94Z in which W represents a direct bond, lower alkylene, thio-lower alkylene or oxy-lower alkylene, and Z represents cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; or R1xe2x80x2 represents a substituent of the formula Bxe2x80x2
in which Axe2x80x2 represents a direct bond, methylene, oxy or thio, p represents zero, one or two and Raxe2x80x2 represents hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen or xe2x80x94Wxe2x80x94Z as defined above; or R1xe2x80x2 represents aryl-hydroxy-lower alkyl in which aryl has meaning as defined above; R3xe2x80x2 represents hydrogen or hydroxy; and R4xe2x80x2 represents hydrogen, lower alkyl, C3-C6-cycloalkyl or hydroxy-lower alkyl; pharmaceutically acceptable prodrug ester derivatives thereof in which one or more free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof.
Preferred are the said compounds of formula I and Ia wherein R3 and R3xe2x80x2, respectively, represent hydroxy, and ester derivatives thereof.
Particularly preferred are the compounds of formula Ia above wherein R3xe2x80x2 represents hydroxy; R4xe2x80x2 represents lower alkyl, cyclopropyl or hydroxy-lower alkyl; and Rxe2x80x2, R1xe2x80x2, Axe2x80x2, p and Ra xe2x80x2 have meaning as defined above; pharmaceutically acceptable prodrug ester derivatives thereof in which free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof.
Further preferred are the compounds of formula II 
wherein Rxe2x80x2 represents hydrogen or C1-C4-alkyl; R1xe2x80x2 represents (C5-or C6)-cycloalkyl-C1-C4-alkyl, or R1xe2x80x2 represents aryl-C1-C4-alkyl in which aryl represents 2- or 3-thienyl, 2-, 3- or 4-pyridyl, phenyl, or phenyl monosubstituted by halogen, trifluoromethyl, lower alkoxy, lower alkyl or by a substituent xe2x80x94Wxe2x80x94Z in which W represents a direct bond, C1-C4-alkylene, thio-C1-C3-alkylene or oxy-C1-C3-alkylene and Z represents cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; or R1xe2x80x2 represents aryl-hydroxy-C1-C4-alkyl in which aryl has meaning as defined above; R4xe2x80x2 represents C1-C4-alkyl, cyclopropyl or hydroxy-C2-C4-alkyl; R5 and R6 represent hydrogen, lower alkanoyl, lower alkoxy-lower alkanoyl, aroyl, carbamoyl, mono- or di-lower alkylcarbamoyl; and pharmaceutically acceptable salts thereof.
Particular preferred are said compounds of formula II wherein Rxe2x80x2 represents C1-C3-alkyl or hydrogen; R1xe2x80x2 represents CH2 CH2-(cyclohexyl or cyclopentyl); or R1xe2x80x2 represents xe2x80x94CH2 CH2-aryl in which aryl represents 2- or 3-pyridyl, phenyl, or phenyl monosubstituted by a substituent xe2x80x94CH2 CH2 xe2x80x94Z or xe2x80x94OCH2xe2x80x94Z in which Z represents cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; R4xe2x80x2 represents ethyl or hydroxyethyl; R5 and R6 represent hydrogen, lower alkanoyl or lower alkoxy-C2-C4-alkanoyl; and pharmaceutically acceptable salts thereof.
Most preferred are the compounds of formula II wherein Rxe2x80x2 represents hydrogen or methyl; R1xe2x80x2 represents cyclohexylethyl; or R1xe2x80x2 represents 2-phenylethyl, 2-(2-pyridyl)-ethyl or 2-phenylethyl substituted in the para position by CH2 CH2 Z in which Z represents carboxy, lower alkoxycarbonyl, carbamoyl or mono-lower alkylcarbamoyl: R4xe2x80x2 represents ethyl: R5 and R6 represent hydrogen; and pharmaceutically acceptable salts thereof.
A particular preferred embodiment of the invention is also represented by the compounds of formula IIa 
wherein R4xe2x80x2 represents ethyl; R5 and R6 represent hydrogen or lower alkanoyl; R7 represents hydrogen or methyl; R8 represents hydrogen or methyl; R9 represents cyclohexyl, phenyl, or phenyl monosubstituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy or xe2x80x94CH2 CH2xe2x80x94Z in which Z represents carboxy or lower alkoxycarbonyl; and pharmaceutically acceptable salts thereof.
The compounds of formula II and IIa as defined above are the most selective adenosine-2 receptor agonists and accordingly are preferred compounds for use in the methods described herein. Particular preferred compounds include those where, in formula I, R represents hydrogen, in formula Ia, Rxe2x80x2 represents hydrogen, in formula II, Rxe2x80x2 represents hydrogen and in formula IIa, R7 represents hydrogen. These are particularly preferred compounds because of their high affinity and selectivity for A2 adenosine receptors. The compound described in Example 2 g is about 100 fold more selective for the A-2 than for the A-1 receptor in vitro. The currently preferred compound is CGS-21680 ((2-p-carboxyethyl)phenylamino-5xe2x80x2-N-carboxamidoadenosine).
Those skilled in the art of organic chemistry will appreciate that reactive and fragile functional groups often must be protected prior to a particular reaction, or sequence of reactions, and then restored to their original forms after the last reaction is completed. Usually groups are protected by converting them to a relatively stable derivative. For example, a hydroxyl group may be converted to an ether group and an amine group converted to an amide or carbamate. Methods of protecting and de-protecting, also known as xe2x80x9cblockingxe2x80x9d and xe2x80x9cde-blocking,xe2x80x9d are well known and widely practiced in the art, e.g., see T. Green, Protective Groups in Organic Synthesis, John Wiley, New York (1981) or Protective Groups in Organic Chemistry, Ed. J. F. W. McOmie, Plenum Press, London (1973).
The general method for preparing the above compounds involves
The compounds of the invention, i.e. of formula I and herein cited derivatives thereof, are preferably prepared by process (a) which comprises condensing a compound of the formula 
wherein R2, R3 and R4 have meaning as defined above and Y represents a leaving group, with a compound of the formula
R1xe2x80x94NHxe2x80x94Rxe2x80x83xe2x80x83IV
wherein R and R1 have meaning as defined above; and, as required, temporarily protecting any interfering reactive group(s) in the starting materials and then subsequently removing the protecting groups to yield a resulting compound of formula I; and, if desired, converting a resulting compound of formula I into another of the invention, and if desired, converting a resulting free compound into a salt or a resulting salt into a free compound or into another salt, and if required, separating any mixture of isomers or racemates obtained into the single isomers or racemates, and if required, resolving a racemate into the optical antipodes.
The compounds described herein may also be prepared by process (b) which comprises condensing a compound of the formula 
wherein R1, R2 and R3 have meaning as defined above, or a reactive functional derivative thereof, with an amine of the formula VI
R4xe2x80x94NH2xe2x80x83xe2x80x83VI
wherein R4 has meaning as defined above; and, as required, temporarily protecting any interfering reactive group(s) in the starting materials and then subsequently removing the protecting groups to yield a resulting compound of formula I; and, if desired, converting a resulting compound of formula I into another of the invention, and if desired, converting a resulting free compound into a salt or a resulting salt into a free compound or into another salt, and if required, separating any mixture of isomers or racemates obtained into the single isomers or racemates, and if required, resolving a racemate into the optical antipodes.
A leaving group in the above processes represents especially halo, for example chloro, bromo or iodo, aliphatically or aromatically substituted sulfonyloxy, for example methylsulfonyloxy or 4-methylphenylsulfonyloxy (tosyloxy), or aliphatically substituted thio, for example lower alkylthio such as methylthio.
In the processes cited herein, reactive functional derivatives of carboxylic acids represent, for example, anhydrides especially mixed anhydrides, acid halides, acid azides, lower alkyl esters and activated esters thereof. Mixed anhydrides are preferably such from pivalic acid, or a lower alkyl (ethyl, isobutyl) hemiester of carbonic acid; acid halides are for example chlorides or bromides; activated esters are for example succinimido, phthalimido or 4-nitrophenyl esters; lower alkyl esters are for example the methyl or ethyl esters.
In starting compounds and intermediates which are converted to the compounds of the invention in a manner described herein, functional groups present, such as amino and hydroxy, are optionally protected by conventional protecting groups that are common in preparative organic chemistry. Protected amino and hydroxy groups are those that can be converted under mild conditions into free amino and hydroxy groups without the molecular framework being destroyed or undesired side reactions taking place.
Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in J. F. W. McOmie, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Plenum Press, London, New York 1973, T. W. Greene, and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Wiley, New York 1984.
For example, a hydroxy group may be protected in the form of esters, e.g. as acyl derivatives such as the lower alkanoyl, benzoyl, benzyloxycarbonyl or lower alkoxycarbonyl esters, or such hydroxy group may be protected in the form of ethers, e.g. as the lower alkyl 1,2-tetrahydropyranyl, trityl or benzyl ethers.
Hydroxy groups on adjacent carbon atoms can also be protected e.g. in the form of ketals or acetals, such as lower alkylidene e.g. isopropylidene, benzylidene or 5- or 6-membered cycloalkylidene e.g. cyclopentylidene or cyclohexylidene derivatives.
In a resulting protected compound of formula I or intermediate, in which one or more of the functional groups are protected, the protected functional groups, e.g. hydroxy groups, can be liberated in a manner known per se, e.g. by means of solvolysis, especially hydrolysis with acid, or by hydrogenolysis.
The preparation of the compounds of the invention according to process a) which involves the displacement of a leaving group Y (e.g. chloro) in a compound of the formula III or a protected derivative by an amine of the formula IV is preferably carried out at elevated temperature, e.g. at a temperature ranging from about 75xc2x0 to 150xc2x0C., with an excess of the amine, in the absence or presence of a solvent, particularly a polar solvent such as dimethylformamide, or under elevated pressure, or in the presence of a base such as triethylamine or potassium carbonate.
The starting materials of formula III can be prepared by condensing a compound of the formula VII 
or a compound of formula VII in partially protected form, wherein X and Y represent a leaving group, and R3 has meaning as defined above, with a compound of the formula VIII
R2xe2x80x94NH2xe2x80x83xe2x80x83VIII
wherein R2 has meaning as defined above; oxidizing the primary alcohol group in a resulting compound of formula IX 
in which any secondary hydroxy groups are in protected form, and wherein Y, R2 and R3 have meaning as defined above, to the corresponding carboxylic acid; and converting said carboxylic acid to a corresponding amide of formula III.
The intermediates of formula VII, and protected derivatives thereof, e.g. in which X and Y represent halogen, particularly chloro, are known or are prepared according to methods known in the art relating to N-(.beta.-D-ribofuranosyl)-purine derivatives, for example as described in Chem. Pharm. Bull. 23, 758 (1975).
The displacement of the leaving group X in a compound of formula VII with an amine of formula VIII is carried out essentially as described above for process (a), preferably using about one mole equivalent of the amine, so as to minimize the displacement of the less reactive leaving group Y.
The oxidation of the resulting e.g. 2-halo substituted adenosine derivatives, in which secondary hydroxy groups are in protected form, is carried out for example with potassium permanganate as described in U.S. Pat. No. 4,167,565.
The resulting carboxylic acid is then first converted to a reactive derivative thereof, e.g. the acid chloride, which is condensed with an amine of the formula VI under condition well-known in the art, e.g. as described in U.S. Pat. No. 4,167,565.
The starting materials of formula IV, VI and VIII are either known in the art, or are prepared using methods known in the art, and as described herein.
The preparation of the compounds of the invention according to process (b) involving the conversion of an acid of formula V to a compound of formula I can be carried out using methodology as described above.
The compounds of the invention or intermediates leading thereto can be converted into other compounds of the invention or corresponding intermediates using chemical methodology known in the art and as illustrated herein.
The conversion of compounds of formula I containing free hydroxy groups to ester derivatives thereof may be carried out by condensation with a corresponding carboxylic acid, advantageously as a reactive functional derivative thereof, according to acylation (esterification) procedures well-known in the art.
A compound of the invention with both 2xe2x80x2 and 3xe2x80x2-hydroxy groups, e.g. a compound of formula I or Ia wherein R3 or R3xe2x80x2 represents hydroxy and wherein both of the adjacent 2xe2x80x2- and 3xe2x80x2-hydroxy groups are protected in the form of ether, acetal or ketal derivatives as described above, e.g. as the isopropylidene (acetonide) derivative, can be converted to a compOund of formula I or Ia wherein R3 or R3xe2x80x2 represents hydrogen by elimination of the 3xe2x80x2-substituent by treatment with a strong base, e.g. sodium hydride in anhydrous isopropanol (sodium isopropoxide) to first yield compound with a double bond between the 3xe2x80x2-4xe2x80x2-carbon atoms, said double bond being subsequently reduced, e.g. by catalytic hydrogenation.
The conversion of the compounds of formula I into pharmaceutically acceptable esters, wherein the 2xe2x80x2-hydroxy group (and 3xe2x80x2-hydroxy group if present) is esterified, can be carried out by condensation with a corresponding carboxylic acid or reactive derivative thereof, according esterification procedures known in the art relating to nucleoside chemistry. For example, an appropriate carboxylic acid anhydride such as acetic anhydride is condensed with a compound of formula I in the presence of asuitable base, e.g. pyridine, triethylamine, 4-(dimethyl-amino)-pyridine, in an inert solvent such as acetonitrile.
A compound of formula I containing a primary amino group (e.g. wherein NRR1 or NHR2xe2x95x90NH2) may be converted to a compound of formula I wherein NRR1 or NHR2 represents a secondary amino group, e.g. wherein R1 or R2 represents e.g. aryl-lower alkyl, by treatment with a reactive derivative of the alcohol corresponding to R1 or R2, e.g. with an aryl-lower alkyl halide such as an aryl-lower alkyl iodide, according to methodology well-known in the art for alkylation of amines. Similarly, a secondary amine wherein R represents hydrogen may be converted to a tertiary amine wherein R represents lower alkyl.
The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures preferably near the boiling point for the solvents used, and at atmospheric or superatmospheric pressure.
The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes. Whenever desirable, the above processes are carried out after first suitably protecting any potentially interfering reactive functional groups, as illustrated herein.
Advantageously, those starting materials should be used in said reactions that lead to the formation of those compounds indicated above as being preferred.
In case diastereomeric mixtures of the above compounds or intermediates are obtained, these can be separated into the single racemic or optically active isomers by methods in themselves known, e.g. by fractional distillation, crystallization or chromatography.
Any racemic products of formula I or basic intermediates can be resolved into the optical antipodes, for example, by separation of diastereomeric salts thereof, e.g., by the fractional crystallization of d- or 1-(tartrate, dibenzoyltartrate, mandelate or camphorsulfonate) salts.
The compounds can be isolated and used in the free form, or as a pharmaceutically acceptable salt. For example, any resulting free base can be converted into a corresponding acid addition salt, preferably with the use of a pharmaceutically acceptable acid or anion exchange preparation, or resulting salts can be converted into the corresponding free bases, for example, with the use of a stronger base, such as a metal or ammonium hydroxide, or any basic salt, e.g., an alkali metal hydroxide or carbonate, or a cation exchange preparation. These or other salts, for example, the picrates, can also be used for purification of the bases obtained; the bases are then first converted into salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
The compounds, including their salts, may also be obtained in the form of their hydrates, or include other solvents used for the crystallization.
The compounds described above are preferably administered in a formulation including an active compound, i.e., a 2-substituted adenosine carboxamide derivative, together with an acceptable carrier for the mode of administration. Suitable pharmaceutically acceptable carriers are known to those of skill in the art.
The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations can include carriers suitable for oral, rectal, topical or parenteral (including subcutaneous, intramuscular and intravenous) administration. Preferred carriers are those suitable for oral or parenteral administration.
Formulations suitable for parenteral administration conveniently include sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient. Thus, such formulations may conveniently contain distilled water, 5% dextrose in distilled water or saline. Useful formulations also include concentrated solutions or solids containing the compounds described herein which upon dilution with an appropriate solvent give a solution suitable for parental administration above.
Alternatively, the compound may be administered in liposomes or microspheres (or microparticles). Methods for preparing liposomes and microspheres for administration to a patient are well known to those of skill in the art. U.S. Pat. No. 4,789,734, the contents of which are hereby incorporated by reference, describes methods for encapsulating biological materials in liposomes. Essentially, the material is dissolved in an aqueous solution, the appropriate phospholipids and lipids added, along with surfactants if required, and the material dialyzed or sonicated, as necessary. A review of known methods is provided by G. Gregoriadis, Chapter 14, xe2x80x9cLiposomes,xe2x80x9d Drug Carriers in Biology and Medicine, pp. 287-341 (Academic Press, 1979). Microspheres formed of polymers or proteins are well known to those skilled in the art, and can be tailored for passage through the gastrointestinal tract directly into the blood stream. Alternatively, the compound can be incorporated and the microspheres, or composite of microspheres, implanted for slow release over a period of time ranging from days to months. See, for example, U.S. Pat. Nos. 4,906,474, 4,925,673 and 3,625,214, the contents of which are hereby incorporated by reference.
Preferred microparticles are those prepared from biodegradable polymers, such as polyglycolide, polylactide and copolymers thereof. Those of skill in the art can readily determine an appropriate carrier system depending on various factors, including the desired rate of drug release and the desired dosage.
The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier and then, if necessary, shaping the product into a desired unit dosage form.
In addition to the aforementioned ingredients, the formulations may further include one or more optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.
The method described herein involve administering 2-substituted adenosine carboxamide derivatives as a pharmacological stressor in conjunction with any one of several noninvasive diagnostic procedures available. For example, intravenous administration may be used in conjunction with thallium-201 myocardial perfusion imaging to assess the severity of myocardial ischemia. Any one of several different radiopharmaceuticals may be substituted for thallium-201 (e.g., rubidium-82, technetium 99 m, derivatives of technetium 99 m, nitrogen- 13, iodine 123, etc.).
In another embodiment, the 2-substituted adenosine carboxamide derivatives may be administered as a pharmacological stressor in conjunction with radionuclide angiography to assess the severity of myocardial dysfunction. In this case, radionuclide angiographic studies may be first pass or gated equilibrium studies of the right and/or left ventricle.
In yet another embodiment, the compounds may be administered as a pharmacological stressor in conjunction with echocardiography to assess the presence of regional wall motion abnormalities.
In still another embodiment, the 2-substituted adenosine carboxamide derivatives may be administered as a pharmacological stressor in conjunction with invasive measurements of coronary blood flow such as by intracardiac catheter to assess the functional significance of stenotic coronary vessels.
Myocardial function can be measured by infusing into a mammal in need of such infusion from about 0.001 to about 1 xcexcg/kg/min of one or more of the compounds described herein. Preferably from about 0.01 to about 1 xcexcg/kg/min is infused, most preferably from about 0.1 to about 1 xcexcg/kg/min.
Various modes of administration are contemplated. These modes include administration in a parenteral dosage form, a sublingual or buccal dosage form, a rectal administration form, or administration by a transdermal device at a rate sufficient to cause vasodilation.
These compounds are used with diagnostic techniques to determine myocardial function. For example, the compounds are useful to image and analyze the vascular capacity of any tissue bed. These compounds can also be used in conjunction with any technique designed to image the heart for the purposes of determining coronary reserve capacity and detecting evidence of coronary heart disease.
This method is also useful to replace adenosine or dipyridamole as pharmacological stressors in thallium-201 scintigraphic diagnosis of coronary function and heart disease. Further, these compounds are useful in imaging any vascular bed and, thus, the vascular function of any organ (eg. heart, brain, kidney, muscle, liver, fetus), in conjunction with any method capable of measuring function in that organ, such as scintigraphy, ultrasound, x-ray, laser, etc.
Typical of the imaging techniques used in practicing the method of the present invention are radiopharmaceutical myocardial perfusion imaging planar (conventional scintigraphy, single photon emission computed tomography (SPECT), position emission tomography (PET), nuclear magnetic resonance (NMR), perfusion contrast echocardiography, digital subtraction angiography (DSA) and ultrafast x-ray computed tomography (CINECT). Performance of these techniques is well known to those of skill in the art.
Typically, the methods involve the intravenous infusion of vasodilatory doses of the compounds (0.0001-1 xcexcg/kg/min) over a short period, followed by the infusion of an imaging agent (e.g., thallium-201), followed by a procedure to detect, record and analyze the image (rotating gamma scintillation analyzer). These dosages are significantly lower than those used when adenosine is administered. There are at least two reasons why this is possible. First, the compounds have significantly longer half-lives than adenosine, and are therefore maintain higher plasma levels. Second, the compounds have significantly higher affinity for the adenosine A2 receptors than adenosine, and therefore, lower concentrations of the compounds are required to achieve the same effect. A further advantage is that the compounds have a lower side effect profile than adenosine due to the high affinity for the adenosine A2 receptors.
The 2-substituted adenosine carboxamide derivatives are also relatively hydrophobic, and should they decompose by way of deribosylation, the resulting adenine derivatives should be less likely to be incorporated into the patient""s genetic material than more hydrophilic derivatives.